title: Innate immunity and primary biliary cirrhosis: activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis.
abstract: Murine models of autoimmunity allow the study of the earliest events in disease pathogenesis. Our laboratory has developed a xenobiotic induced model of primary biliary cirrhosis (PBC) following immunization of mice with 2-octynoic acid coupled to bovine serum albumin (2-OA-BSA), an antigen selected following quantitative structure-activity relationship analysis of the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the immunodominant autoantigen of PBC. Recent data in humans with PBC has suggested that a major component of liver pathology is due to activation of innate immunity. We took advantage of our 2-OA-BSA model and immunized mice with and without the addition of α-galactosylceramide (α-GalCer), an invariant natural killer T cell activator. Importantly, we report herein that 2-OA-BSA-immunized mice exposed to α-GalCer develop a profound exacerbation of their autoimmune cholangitis, including significant increases in CD8(+) T-cell infiltrates, portal inflammation, granuloma formation, and bile duct damage. Furthermore, such mice produce increased levels of antimitochondrial antibodies and have evidence of fibrosis, a feature not previously reported in the murine models of PBC.
  
  
  CONCLUSIONS
  Our data suggests a primary role of innate immunity in the exacerbation of autoimmune cholangitis and also become a logical explanation for the recurrence of PBC following liver transplantation in the absence of major histocompatability complex compatibility. We submit that PBC begins with loss of tolerance to PDC-E2 and a multilineage antimitochondrial response in which autoreactive CD8(+) T cells are critical. However, the perpetuation of disease and its exacerbation will also be modulated by innate immune mechanisms.
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Si-Jie
authors.initials: SJ
authors.lastname: Wu
authors.forename: Yao-Hsu
authors.initials: YH
authors.lastname: Yang
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.forename: Petr
authors.initials: P
authors.lastname: Illarionov
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chuang
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D002761:Cholangitis / Q000276:immunology*; D004195:Disease Models, Animal; D005229:Fatty Acids, Monounsaturated; D005260:Female; D007113:Immunity, Innate; D008103:Liver Cirrhosis / Q000276:immunology*; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000276:immunology; D055611:Natural Killer T-Cells / Q000276:immunology*
chemical_list: D005229:Fatty Acids, Monounsaturated; C060855:2-octynoic acid